The term biodegradable polymers refers to those polymers which are slowly converted to nontoxic degradation products in the body. Examples of biodegradable polymers include polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxybutyrate, polyhydroxyvalerate, poly(alkylcyanoacrylate), polyanhydrides, polyorthoesters, poly(aminoacids), pseudopolyamino acids, polyphosphazenes. Some of these polymers and their copolymers have been studied extensively for biomedical applications such as sutures, staples and mesh for wound closure, fracture fixation, bone augmentation and ligament reconstruction in orthopedics, ligation clips and vascular grafts in cardiovascular surgery, and dental repairs (Barrows T. Degradable implant materials: a review of synthetic absorbable polymers and their applications. Clinical materials., 1:233-257, 1986). They have also been used to prepare biodegradable drug delivery systems capable of releasing the drug or a biologically active substance over the desired length of time.
The advantages of using biodegradable polymers in biodegradable delivery systems of BAS are: ready availability of polymers, polymers used are nontoxic, biocompatibile and biodegradable, facile predictability of biodegradation rates of the polymers, ease of modification of the degradation characteristics of the polymers, regulatory approval of some of the commonly used biodegradable polymers, ease of fabrication of the polymers into various types of devices and the possibility of controlling the release of BAS by polymers over the desired length of time.
Release of a BAS from a polymeric delivery system depends on the physicochemical characteristics of the BAS molecule, polymer and other excipients, and the dosage form. The important factors governing BAS release characteristics from the delivery systems prepared with biodegradable polymers are polymer molecular weight, copolymer ratio, polymer hydrophilicity or lipophilicity, degree of plasticization, particle size and percentage of BAS-loading, hydrophilicity or lipophilicity of the incorporated BAS, solubility of the BAS in both the delivery system and in the biological fluids, physical form of the formulation (i.e. solution, suspension, gel or paste), and the method of preparation of the delivery system.
Several types of BAS delivery systems have been prepared from biodegradable polymers. These include microparticles such as microspheres and microcapsules (Schindler A, Jeffcoat R, Kimmel G L, Pitt C G, Wall M E and Zwelinger R., in: Contemporary Topics in Polymer Science, Pearce E M and Schaefgen J R, eds., Vol. 2, Plenum Publishing Corporation, New York, pp. 251-289, 1977; Mason N S, Gupta D V S, Keller, D W, Youngquist R S, and Sparks R F. Biomedical applications of microencapsulation, (Lim F, ed.), CRC Press Inc., Florida, pp. 75-84, 1984; Harrigan S E, McCarthy D A, Reuning R and Thies C., Midl. Macromol. Monograph, 5:91-100, 1978. ; Sanders L M, Burns R, Bitale K and Hoffman P., Clinical performance of nafarelin controlled release injectable: influence of formulation parameters on release kinetics and duration of efficacy., Proceedings of the International Symposium on Controlled Release and Bioactive Materials, 15:62-63, 1988; Mathiowitz E, Leong K and Langer R., Macromolecular drug release from bioerodible polyanhydride microspheres, in: Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, Peppas N and Haluska R, eds., pp. 183, 1985), films (Jackanicz T M, Nash H A, Wise D L and Gregory J B. Polylactic acid as a biodegradable carrier for contraceptive steroids., Contraception, 8:227-233, 1973. ; Woodland J H R, Yolles S, Blake A B, Helrich M and Meyer F J. Long-acting delivery systems for narcotic antagonist. I. J. Med. Chem., 16:897-901, 1973), fibers (Eenink M J D, Maassen G C T, Sam A P, Geelen J A A, van Lieshout J B J M, Olijslager J, de Nijs H, and de Jager E. Development of a new long-acting contraceptive subdermal implant releasing 3-ketodesogeatrel., Proceedings of the 15th International Symposium on Controlled Release of Bioactive Materials, Controlled Release Society, Lincolnshire, Ill., pp.402-403, 1988), capsules (Sidman K R, Schwope A D, Steber W D, Rudolph S E, Paulin S B. Biodegradable, implantable sustained release systems based on glutamic acid copolymers. J. Membr. Sci., 7:277-291, 1980; Pitt C G, Gratzl M M, Jeffcoat M A, Zweidinger R and Schindler A. Sustained drug delivery systems II: Factors affecting release rates from poly-.epsilon.-caprolactone and related biodegradable polyesters., J. Pharm. Sci., 68(12):1534-1538, 1979), discs (Cowsar D R, Dunn R L., Biodegradable and non-biodegradable fibrous delivery systems, in: Long acting Contraceptive Delivery Systems, Zatuchni G I, Goldsmith A, Shelton J D and Sciarra J J, eds., Harper & Row, Publishers, Philadelphia, pp.145-148, 1984), wafers (Brem et al., J. Neurosurgery, 74:441-446, 1991), and solutions (Dunn et al., U.S. Pat. Nos. 4,938,763; 5,324,519; 5,324,520; 5,278,201; 5,340,849; 5,368,859; 5,660849; 5,632,727; 5,599,552; 5,487,897). All of these, with the exception of microparticles and solutions, need to be surgically implanted. This procedure is inconvenient and undesirable. Drug-loaded microspheres and solutions, on the other hand, can be easily injected. However, there are several inherent disadvantages of microparticles. These include the need for reconstitution before injection, the inability to remove the dose once it is injected, and the relative complicated manufacturing procedure.
While solutions described in patents by Dunn et al. offer the distinct advantage of ease of injection, an inherent disadvantage to the method of preparing solutions, as indicated in the patents is that, the amount of polymer which can be incorporated into n-methylpyrrolidone (NMP), the solvent of choice cited in their inventions, appears to be limited. This is particularly true when higher concentrations of high molecular weight polymers have to be dissolved in NMP by the method cited in the patents by Dunn et al. Therefore, there clearly exists a need for developing easily injectable, implantable or applicable biodegradable BAS delivery systems such as free-flowing and viscous liquids, gels, and pastes prepared from biodegradable polymers using alternative methods.